1. Field of the Invention
The present invention is related to novel uses of n-butylidenephthalide (abbreviated as n-BP hereinafter) in treating a liver injury such as liver fibrosis, liver cirrhosis or hepatitis, and in restoring/improving liver function after liver function adversely affected by a liver injury.
2. Descriptions of the Related Art
Liver fibrosis or more severe form, cirrhosis, is liver cells response to extrinsic injury from a variety of viral, toxin or metabolic insults. Cirrhosis is responsible for as many as 35 000 annual deaths in the United States, unless the progressive degeneration in liver function can be rescued with liver transplantation. Histologically, cirrhosis is characterized by excessive extracellular matrix deposition (i.e. fibrosis), which surrounds regenerative hepatocellular nodules.
In addition to deterioration in liver function, these nodules are also a seedbed for the formation of hepatocellular carcinoma. Clinically, Silymarin and Pentoxifylline (Trental) can significantly reduce the mortality of patients with alcoholic-induced liver cirrhosis. However, there is only ambiguous efficacy to attenuate liver fibrosis and improve liver function (Zhang et al., 2005)1. Therefore, effective medicines, foods or substances that can attenuate progression or induce regression of liver fibrosis are important.
Angelica sinensis (also known as Dong Quai) is indicated for menstrual disorders, including menopausal symptoms (Huntley and Ernst, 2003)2. It has also been widely used for conditions such as gastric mucosal damage, hepatic injury, impaired myocardial blood flow, and chronic glomerulonephritis (Yim et al., 2000, Ye et al., 2001a, Ye et al., 2001b)3-5. Furthermore, Dong Quai has been promoted in the United States for treatment of several gynecologic disorders (Abebe, 2002)6.
Six major compounds have been isolated from Angelica sinensis: (E)-liguistilide, (Z)-liguistilide, n-butylidenephthalide, palmitic acid, b-sitosterol, and ferulic acid. n-butylidenephthalide (n-BP molecular weight,—188.22) and liguistilide (K2; molecular weight,—190.23) are particularly abundant (Wang et al., 1998)7, with the former exhibiting more potency than ligustilide. In conscious rats, n-BP relieves angina without affecting blood pressure or the heart rate (Ko et al., 1998, Chan et al., 2009)8-9. Previously, we demonstrated that the acetone extract of A. sinensis inhibits the proliferation of cancer cells in vitro (Cheng et al., 2004)10 and that the subsequently obtained chloroform extract of A. sinensis antagonizes brain tumor cells in vitro and in vivo (Tsai et al., 2006)11. We also demonstrated that the antitumor effects of n-BP on neuroblastoma, lung cancer, melanoma, teratoma, leukemia, breast cancer, and hepatocellular carcinoma in vitro and on GBM brain tumors both in vitro and in vivo. However, so far, there is no any study for n-BP against liver fibrosis or cirrhosis.
Liver fibrosis is the common consequence of different liver diseases characterized by chronic liver tissue damage. This process is a consequence of chronic activation of hepatic stellate cells (HSC), leading to cell proliferation and increased deposition of extracellular matrix components.